By David N. Leff

Anyone growing or stashing the marijuana plant (Cannabis sativa) or any of its spin-offs ¿ pot, reefers, joints, hash et. al ¿ is asking for trouble with the law. Yet every man, woman and child on earth carries a well-hidden cache of a cannabis-like substance in his or her brain.

What can such a privileged cerebral organ be up to ¿ sequestering the biochemical basis of a legally banned substance? For one thing among many, these endogenous cannabinoids jump-start the human appetite for food. Carried too far, this urge to splurge on munchies can lead to obesity. But not to worry; the brain also responds to a countervailing agent, namely leptin, which famously curbs food hunger.

¿That cannabinoids improve appetite is nothing new,¿ observed research pharmacologist George Kunos. ¿Millions of people who at one time or another smoked pot know about its food-craving effect. Our research provided evidence that the endogenous counterparts of marijuana, produced in the brain, have a similar impact. Moreover it also showed that at least in the animal models in which we tested it, they are part of the normal neural circuitry, which includes leptin, that controls food intake and appetite.¿

A recent issue of Nature, dated April 12, 2001, connects these two dots in a paper titled: ¿Leptin-regulated endocannabinoids are involved in maintaining food intake.¿ Its senior author is Kunos, scientific director at the National Institute on Alcohol Abuse and Alcoholism.

¿Genetically engineered modified mice,¿ he recounted, ¿lack the receptor on brain cells that recognizes both the synthesized cannabinoids and the endogenous compounds. When the animals¿ appetite was increased by brief food deprivation, they ate less than the normal mice that had the receptor. Moreover, we could reduce the food intake in the normal animals by giving them a drug that blocks the receptor, whereas in the mutant animals that compound was ineffective.

¿That drug,¿ Kunos continued, ¿called SR141716A, is a selective antagonist that blocks the brain-type cannabinoid receptor. It was developed several years ago by a French company, Sanofi SA, in Paris, to focus its efforts on cannabinoids. SR141716A is a synthetic compound, and just to demonstrate that blocking its effect can be exploited in human therapy, this company has it in clinical trials. These have been going on for over two years now, and I heard from Sanofi they¿re not over yet. But they¿ve got encouraging interim results, showing that it does reduce both food intake and weight in obese human subjects.¿

Cannabis Blocker Inhibits Appetite Too

Kunos was led to his inquiry by the similarity between the symptoms of leptin deficiency and the symptoms of cannabinoid treatment. It suggested that they have mutually antagonistic activity profiles.

¿We know that leptin is a major regulator of food-intake circuitry,¿ he pointed out. ¿It¿s released from fat tissue, and informs the brain of the status of body fat. Leptin reduces food intake by acting on receptors in the brain¿s hypothalamus. It does this by decreasing production of certain neuropeptides that are promoting food intake and appetite.

¿So we wondered,¿ Kunos recounted, ¿whether leptin may also regulate endogenous cannabinoid. A first point raised in our Nature paper is that food intake is such a vital function in the body that there is a significant redundancy in the brain. That is, there are many other potent stimulants of food intake, of which the best known is neuropeptide Y. It also increases the production of other peptides that boost appetite. These are the orexigens. So neuropeptide Y acts like an orchestra conductor, the first among equals that coordinates the whole circuitry. We tested the hypothesis that if we block one, the others might compensate. We found that cannabinoids are not the ones that compensate for the loss of neuropeptide Y.¿

French Obesity Drug In Closely Held Clinicals

¿This also suggests,¿ Kunos continued, ¿that it would probably be unrealistic to expect a major effect on food intake ¿ as in obese people ¿ by just blocking one pathway. So, you may need to use a combination of drugs blocking several pathways to have a therapeutically important effect. Sanofi¿s clinical trial is ongoing, and the company obviously senses commercial promise in this.

¿We are working on other compounds,¿ Kunos said, ¿that have a similar pharmacological activity, and we are planning to develop alternative antagonists. Drugs that would block the cannabinoid receptors in the future would have promise in the treatment of obesity.¿

As for potential addictiveness, Kunos said, ¿If we treat animals with cannabinoids, and then give them this receptor-blocking drug ¿ which would displace the cannabinoids from the receptors ¿ we can actually precipitate withdrawal, direct evidence of their addictive property. Therefore, I think the more immediate promise is the use of drugs that block the cannabinoid receptors, because they obviously aren¿t addictive. Moreover, these drugs ¿ based on what they do, such as antagonizing the effects of cannabinoids ¿ have promise in treating obesity, either alone or more likely in combination with other drugs that block the pathway.¿

Ways Around Addiction Issue

¿The more controversial issue,¿ he pointed out, ¿is the opposite: whether you can treat these patients diagnosed with other types of eating disorders, such as anorexia or AIDS-related appetite loss. There is anecdotal evidence that smoking marijuana can substantially help these people. But that¿s not acceptable by society¿s standards.

¿However, even there,¿ Kunos suggested, ¿there¿s some possibility. Instead of treating them with marijuana or marijuana-like addictive substances, you can target the brain¿s own endogenous cannabinoid system, by trying to develop drugs that block the enzyme that normally degrades these substances. That would actually enhance the activity of those endogenous agents. Yet, even that is not without problems, because you may still not be able to avoid the psychoactive affects. But at least you are working with an endogenous substance, not a drug of abuse.

¿I would just say,¿ he concluded, ¿that drugs that influence the endogenous cannabinoid signaling system ¿ receptor blockers, agents that selectively block the degrading enzymes, crystallographic study of amino hydrolase ¿ have potential therapeutic usefulness.¿

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